Presenilin-1 (PS-1; STM-1; E5-1; AD) Ca2+ leak channel (part of the γ-secretase complex; expression alters the lipid raft composition in neuronal membranes (Eckert and Müller, 2009)). The first 5 TMSs of presenilin-1 are homologous to the 5 TMS CD47 antigenic protein, a constituent of the osteoclast fusion complex (1.N.1.1.1), and CD47 is therefore a presenilin homologue (unpublished observations). The active site of gamma-secretase resides in an aqueous catalytic pore
within the lipid bilayer and is tapered around the catalytic aspartates
(Sato et al. 2006). TMS 6 and TMS 7 contribute to the hydrophilic pore. Residues at the luminal portion of TMS 6 are predicted to form a subsite for substrate or inhibitor binding on the α-helix facing the hydrophilic milieu, whereas those around the GxGD catalytic motif within TMS 7 are water accessible (Sato et al. 2006).

Archaeal presenilin homologue (DUF1119; COG3389; PSN). Members of the peptidase A22B superfamily (found in many archaea, but not bacteria, shows some sequence similarity to members of the LIV-E family, e.g., 2.A.78.2.1))

Presenilin homologue (DUF1119) of 301 aas and 9 TMSs with known 3-d structure. The amino-terminal domain, consisting of TM1-6, forms a horseshoe-shaped
structure, surrounding TM7-9 of the carboxy-terminal domain. The two
catalytic aspartate residues are located on the cytoplasmic side of TMS 6
and TMS 7, spatially close to each other and approximately 8 Å into the
lipid membrane surface. Water molecules gain constant access to the
catalytic aspartates through a large cavity between the amino- and
carboxy-terminal domains. (Li et al. 2013). Both protease and ion channel activities have been demostrated, and these two activities share the same active site (Kuo et al. 2015). Cleavage is controlled by both positional and chemical factors (Naing et al. 2018).

Signal peptide peptidase, SppL3 of 385 aas and 9 TMSs. Cleaves the single TMS in the neuronal ceroid lipofuscinoses (NCLs), a group of proteins causing recessive disorders of childhood with overlapping symptoms including vision loss, ataxia, cognitive regression and premature death (Jules et al. 2017). CLN5 is implicated in the recruitment of the retromer complex to endosomes, which is required to sort the lysosomal sorting receptors from endosomes to the trans-Golgi network. It is initially translated as a type II transmembrane protein and subsequently cleaved by SPPL3 into a mature soluble protein consisting of residues 93-407 and an N-terminal fragment is then further cleaved by SPPL3 and SPPL2b and degraded in the proteasome (Jules et al. 2017).

The pre-flagelin peptidase of 230 aas and 6 TMSs, FlaK, with known 3-d structure (3.6Å resolution) (Hu et al. 2011). This protein is a member of the presenilin/GxGD membrane protein family; it plays a dual role as protease and ion-conducting channel and is therefore called a "channzyme" (Kuo et al. 2015).